It is estimated that 169,400 patients will be diagnosed with lung cancer in the United States in 2002, and 154,900 will die as a result of the disease. Non-small-cell carcinomas (NSCLC) account for 85% of cases, and are predominantly adenocarcinomas, squamous cell carcinomas, or large cell carcinomas. Even though 5-year survival rates have improved from 8% in the early 1960s to 15% in the early 1990s there is still considerable room for improvement. In early clinical stages surgical resection alone offers poor long-term survival. For pathologic stages IA, IB, IIA, and IIB, 5-year survivals are approximately 70%, 60%, 55%, and 40%, respectively. When the tumor has spread to the ipsilateral mediastinal lymph nodes (N2 disease), 5-year survival is 13%, and when contralateral lymph nodes (N3 disease, stage IIIB) are involved, it is only 5%. Most of the recurrences are distant highlighting the fundamentally systemic nature of the disease. Attempts to improve survival by postoperative chemotherapy, radiation, or both in resectable NSCLC have been uniformly dismal.
A better understanding of the biology of NSCLC could enable doctors to predict for recurrence and may also be useful to select the therapeutic intervention with optimal impact on recurrence, survival, and quality of life. Proteins of the nucleotide excision repair pathway are thought to repair DNA damage caused by platinum agents. The excision repair cross-complementing (ERCC) gene family reduces damage to DNA by nucleotide excision and repair. Modified nucleotides together with adjacent nucleotides are removed from the damaged strand during the first step (excision), which is followed by synthesis of an intact strand through DNA polymerase activity (repair synthesis). The ERCC1 gene encodes a protein of 297 amino acids that is considered to function in a complex with ERCC11, XPF, and ERCC4. This complex may be required in both recombinatorial repair and nucleotide excision repair and impaired function could lead to increased genomic instability and a more malignant phenotypic behavior of tumors. The predominant type of genome instability in cancer is structural aberration of chromosomes (ie, deletions, translocations, and insertions). These are thought to arise as a result of impaired repair of DNA double-strand breaks by homologous recombination and nonhomologous end joining.